The essential feature of this Program-Project proposal is its emphasis upon collaborative efforts between basic neurobiologists and clinical researchers, working together toward an elucidation of neurobiological factors in the genesis and treatment of major psychiatric disorders. The basic science section of the program is divided into two parts: 1) central neurotransmitters, receptors, and drugs; and 2) neurobiological processes in animal behavior. The central neurotransmitters to be investigated most intensively are the monoamines (norepinephrine, dopamine and serotonin) and acetylcholine. In relation to these neurotransmitter systems, drugs have been selected for study that are of major importance in psychiatry; these include antipsychotic, antidepressive, and psychotomimetic drugs. The animal behavioral studies, many of which also involve the above drugs and neurotransmitter systems deal with aggression, habituation, and animal models of affective disorders. The basic neurobiological aspects of the program, which provide for the development of anatomical, histochemical, biochemical, and neurophysiological techniques, form an essential groundwork for the behavioral studies. The other major subdivision of the proposed program involves clinical investigations into: 1) biological processes which may be related to the genesis of schizophrenia and the affective disorders; and 2) biological predictors of treatment response in the above disorders. The anticipated interaction between the basic neurobiological and clinical areas is twofold. Direct measures of neurotransmitter metabolism or neurophysiological response (e.g. measured with depth electrodes) in the animal studies can provide a basis for interpreting less direct measures in patients (e.g., amine metabolites or surface potentials). Secondly, drugs of emerging clinical interest can be tested in the animal systems and, conversely, drugs which appear to have clinical potential on the basis of their properties in animal model systems can ultimately receive early clinical trials.